This is a revised competitive renewal for CA80964 - Mechanisms that regulate tumor-specific immune responses. In the past 5 years we have made considerable progress on the aims of our previous proposal and acquired a number of insights that we consider to be highly relevant to improving the treatment of patients with cancer. These insights pertain to the three different areas noted below. The overarching hypothesis of this proposal is that tumors fail to regress, or progress following initial regression, because of the presence of active, potent suppressive mechanisms and/or the failure to maintain adequate numbers of therapeutic T cells in the cancer-bearing host. Building on our progress, we propose to address the following three specific aims: Aim 1: To investigate the mechanisms responsible for the loss of therapeutic anti-tumor function following multiple vaccinations and identify strategies to boost anti-tumor immunity without loss of therapeutic function. Aim 2: To investigate the mechanisms responsible for tumor recurrence after successful immunotherapy and develop methods to prevent/treat tumor recurrence. Aim 3: To evaluate whether proteasomal-dependant regulation of immune targets represents a novel immune escape mechanism and develop strategies to treat antigen-loss variants. IMPACT: Translation of Laboratory results to the clinic: Since 2007 we have completed two pilot clinical trials that combined chemotherapy-induced lymphodepletion with adoptive transfer of PBMC (reconstitution) and vaccination with encouraging results. The preclinical platform for these trials was developed in the prior funding cycle of this award. In early 2009 we opened 2 new investigator-initiated clinical trials based on findings supported by this award. A third investigator-initiated FDA-approved clinical trial has been held back because of vaccine issues and the CD4-depletion study, mentioned above, is awaiting availability of Zanolimumab (humanized anti-CD4 in Phase III clinical trials). PUBLIC HEALTH RELEVANCE: Recent advances in the field of tumor immunotherapy have provided "improved" vaccination strategies for patients with cancer. However, when these strategies were tested in large phase III clinical trials, they failed to improve patient outcomes. Recent work from our group has identified that multiple administrations of cancer vaccines, instead of boosting the immune response, turns the immune system off. Further, tumors also induce suppressive mechanisms that counteract the potential benefits of vaccines. Recent data from our laboratory suggests ways to overcome these suppressive influences;resulting in complete regression of large tumors and high rates of cure. Here we propose to investigate strategies to further improve on these results and generate data that will pave-the-way for a series of new clinical trials for patients with advanced cancer.